Method for treating tinnitus aureum

ABSTRACT

A method is described for treating tinnitus aureum in a subject by administering to the subject a therapeutically effective amount of a compound as defined in Formula I herein, illustratively (R)-2-acetamido-N-benzyl-3-methoxypropionamide, or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of co-pending applicationSer. No. 10/466,295 which is a national stage entry under 35 U.S.C. §371of International Application No. PCT/EP2002/03032 filed on 19 Mar. 2002,which claims the benefit of European Application No. 01107026.5 filed on21 Mar. 2001. Each of the above referenced applications is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to the novel use of a group of specificamino acid derivatives according to Formula I for the preparation ofpharmaceutical compositions useful for the treatment of allodynia as amajor and unique pain symptom independent of the nature of an underlyingdisease, but that is often related to neuropathic pain or otherdifferent types of chronic or phantom pain. Particularly the presentinvention relates to the novel use of harkoseride and its derivativesfor the preparation of pharmaceutical compositions useful for thetreatment of allodynia as a major and unique pain symptom independent ofthe nature of an underlying disease, but that is often related toneuropathic pain, or other different types of chronic or phantom pain.

The chemical name of SPM 927 which is also hereinafter referred to asharkoseride is (R)-2-acetamido-N-benzyl-3-methoxypropionamide.

The compounds of the invention are known agents useful in antiseizuretherapy for central nervous system disorders such as epilepsy, strokeand cerebral ischemia.

The instant invention concerns the novel use of a compound of Formula Ibelow for the preparation of pharmaceutical compositions useful for thetreatment of pain, particularly for the treatment of chronic paindisorders and especially for the treatment of allodynia as a major andunique pain symptom independent of the nature of an underlying disease,but that is often related to neuropathic pain conditions, or otherdifferent types of chronic or phantom pain and tinnitus aureum.

According to the invention compounds are those of Formula I

or a pharmaceutically acceptable salt thereof, wherein

-   Ar is phenyl which is unsubstituted or substituted with at least one    halo group;-   Q is lower alkoxy containing 1-3 carbon atoms and Q₁ is methyl;    diastereomers and enantiomers of compounds of Formula I are included    in the invention.

Preferred compounds of the invention are those according to Formula I inwhich the compounds are an (R), (S), or (R,S) isomer.

The most preferred compound of the invention is(R)-2-acetamido-N-benzyl-3-methoxypropionamide or its pharmaceuticallyacceptable salt thereof.

Pain is a subjective experience and the perception of pain is performedin particular parts of the Central Nervous System (CNS).

Usually noxious (peripheral) stimuli are transmitted to the CentralNervous System beforehand, but pain is not always associated withnociception.

A broad variety of different types of clinical pain exists, that arederived from different underlying pathophysiological mechanisms and thatwill need different treatment approaches.

The perception of pain may be characterized by three major types ofclinical pain:

-   -   acute pain    -   chronic pain    -   neuropathic pain

Acute clinical pain typically results from inflammation or soft tissueinjury. This type of pain is adaptive and has the biologically relevantfunction of warning and enabling healing and repair of an alreadydamaged body part to occur undisturbed. A protective function isachieved by making the injured/inflamed area and surrounding tissuehypersensitive to all stimuli so that contact with any external stimulusis avoided. The neuronal mechanisms underlying this type of clinicalpain are fairly well understood and pharmacological control of acuteclinical pain is available and effective by means of e.g. Non-SteroidalAnti-Inflammatory Drugs (NSAIDs) up to opioids depending on type andextension of the sensation.

Chronic clinical pain appears as sustained sensory abnormalitiesresulting from an ongoing peripheral pathology such as cancer of chronicinflammation (e.g. arthritis) or it can be independent of the initiatingtriggers. The latter being maladaptive, offering no survival advantageand very often no effective treatment is available.

Neuropathic pain is caused by injury or infection of peripheral sensorynerves. It includes, but is not limited to pain from peripheral nervetrauma, herpes virus infection, diabetes mellitus, causalgia, plexusavulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain isalso caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

Neuropathic pain shows two different pathophysiological mechanisms whichhave to be considered:

First, enhanced activity of afferent nociceptive neurons followingsensitization of (sleeping) neurons (e.g., inflammatory pain, cancerpain, headache, lower back pain, visceral pain, migraine) with theprimary afferent nociceptive neuron remaining intact, though thereceptor activity is changed and reduced thresholds, increase of firingrates and starting of or increase of spontaneous activity are typicallyfound.

Second, ectopic activity of afferent nociceptive neurons followinglesions of its axons (e.g., peripheral and central neuropathic pain),with the primary afferent neuron being damaged. This leads toirreversible peripheral and central biochemical, morphological andfunctional changes. Therefore, (peripheral) neuropathy is broadlydefined as a disease of the (peripheral) nervous system.

There are several causes of human neuropathy with considerablevariability in symptoms and neurological deficits. Painful neuropathiesare defined as neurological disorders characterised by persistence ofpain and hypersensitivity in a body region, of which the sensoryinnervation has been damaged, but damage to sensory nerves does notalways produce neuropathic pain, usually loss of sensation rather thanhypersensitivity or pain are observed.

Specific somatosensory disorders are referred to as allodynia (innocuoussomatosensory stimulation evokes abnormal intense pain sensation with anexplosive, radiating character often outlasting stimulus duration like atrigger), hyperalgesia (noxious stimulation evokes more intense andprolonged pain sensations), paresthesia (spontaneous aversive butnonpainful sensations, described as tingling or “pins and needles”),dysesthesia (evoked as well as spontaneous abnormal sensations).

Several key events are agreed in as common pathophysiological events ofabnormal pain states particularly following peripheral nerve injury.Thus, high frequency spontaneous discharge from ectopic site is followedby an increased responsiveness of dorsal horn neurons and expansion ofthe receptive field, often defined as central sensitisation.

Common analgesics like opioids and non-steroidal anti-inflammatory drugs(NSAIDs) improve only insufficiently chronic abnormal pain syndromes. Inthe search for alternative treatment regimes to produce satisfactory andsustained pain relief, corticosteroids, conduction blockade, glycerol,antidepressants, local anesthetics, gangliosids and electrostimulationhave been tried, but mainly anti-convulsants have been found usefulagainst various types of neuropathic pain conditions, but appear to bemost effective in cases of paroxysmal, lancinating events, e.g.trigeminal neuralgia.

If general overactivity and unleaded low threshold activation of sensoryneurons is considered as one of the main syndromes of neuropathy andneuropathic pain sensation with a marked mechanoallodynia as the mostdisabling clinical symptom, selective inhibition of thispathophysiological event instead of general inhibition of high thresholdnoxious stimuli (by e.g. local anesthetics) of the normal sensorynociception provides clear advantages.

The conditions listed above are known to be poorly treated by currentlymarketed analgesics such as opioids or non-steroidal anti-inflammatorydrugs (NSAIDs) due to insufficient efficacy or limiting side effects.

It is an object of this invention to provide a novel use of compoundsaccording to the aforementioned Formula I and its derivatives for thepreparation of pharmaceutical compositions useful for the treatment ofallodynia as a major and unique pain symptom independent of the natureof an underlying disease, but that is often related to neuropathic pain,or other different types of chronic or phantom pain.

Particularly it is an object of this invention to provide a novel use ofharkoseride for the preparation of pharmaceutical compositions usefulfor the treatment of allodynia as a major and unique pain symptomindependent of the nature of an underlying disease, but that is oftenrelated to neuropathic pain, or other different types of chronic orphantom pain.

Harkoseride, which chemical name is(R)-2-acetamido-N-benzyl-3-methoxypropion-amide is one derivativeselected of the group of specific amino acid derivatives.

This group of substances is disclosed in U.S. Pat. No. 5,378,729; U.S.Pat. No. 5,654,301 and U.S. Pat. No. 5,773,475. They show activity forthe treatment of epilepsy and stroke. But there is no disclosure in theabove references to make obvious the present invention.

The compounds of the present invention may form pharmaceuticallyacceptable salts with both organic and inorganic acids or bases.

For example, the acid addition salts of the basic compounds are preparedeither by dissolving the free base in aqueous or aqueous alcoholsolution or other suitable solvents containing the appropriate acid andisolating the salt by evaporating the solution.

Examples of pharmaceutically acceptable salts are hydrochlorides,hydrobromides, hydrosulfates, etc. as well as sodium, potassium, andmagnesium, etc. salts.

The compounds of the present invention can contain one or severalasymmetric carbon atoms. The invention includes the individualdiastereomers or enantiomers, and the mixtures thereof. The individualdiastereomers or enantiomers may be prepared or isolated by methodsalready well-known in the art.

According to the invention it is preferred that the compounds are in the(R)-configuration. It is preferred that the compounds are substantiallyenantiopure. Most preferred is the compound(R)-2-Acetamido-N-benzyl-3-methoxypropionamide.

The compounds of this invention may be synthesized as disclosed in U.S.Pat. No. 5,378,729; U.S. Pat. No. 5,654,301 and U.S. Pat. No. 5,773,475.

The compounds made by the synthetic methods can be used aspharmaceutical compositions as agent in the treatment of pain when aneffective amount of a compound of the Formula I, together with apharmaceutically acceptable carrier is used. The pharmaceutical can beused in a method for treating such disorders in mammals, includinghuman, suffering therefrom by administering to such mammals an effectiveamount of the compounds described above in unit dosage form.

The pharmaceutical compound, made in accordance with the presentinvention, can be prepared and administered in a wide variety of dosageforms by either oral or parenteral routes of administration. Forexample, these pharmaceutical compositions can be made in inert,pharmaceutically acceptable carriers which are either solid or liquid.Solid form preparations include powders, tablets, dispersible granules,capsules, cachets, and suppositories. Other solid and liquid formpreparations could be made in accordance with known methods of the artand administered by the oral route in an appropriate formulation, or bya parenteral route such as intravenous, intramuscular, or subcutaneousinjection as a liquid formulation.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 2×300 mg per day perpatient. A daily dose range of about 1 mg to about 300 mg is preferred.The dosages, however, may be varied depending upon the requirement witha patient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for particularsituations is within the skill of the art.

The following working examples selected from specific animal models showthe antineuropathic pain activity of harkoseride and its derivatives ingeneral and the antiallodynia efficacy of harkoseride and itsderivatives in particular.

EXAMPLE 1

Formalin Test, Rat

Significant and dose dependent efficacy of harkoseride could bedemonstrated in the late phase of the rat formalin test.

The formalin test is a chemically-induced tonic pain model in whichbiphasic changes of nociceptive behavior are assessed andspinal/supraspinal plasticity of nociception is considered as amolecular basis for neuropathic pain particularly during the second(=late) phase of the test, during which most clinically used drugsagainst neuropathic pain are active. These features have resulted in theformalin test being accepted as a valid model of persistent clinicalpain.

The compound was tested for anti-nociceptive properties by use of theweighted behavioral scoring method: Freely moving animals underwentobservational assessment of the position of the left hind paw accordingto a rating score scaled 0-3 before and 10, 20, 30 and 40 minutes afterinjection of 0.05 ml of sterile 2.5% formalin under the skin on thedorsal surface of the paw. Harkoseride, administered i.p. just prior toformalin injection produced dose dependant reduction of theformalin-induced tonic inflammatory nociceptive behavior as shown inTable 1 (weighted pain scores±SEM, n=11-12/group).

TABLE 1 Weighted pain score, formalin test, rat Dose No. of Time AfterInjection of formalin and SPM 927 [mg/kg] Animals BASELINE 10 MIN 20 MIN30 MIN 40 MIN 0 11 0.00 ± 0.00 0.30 ± 0.16 0.93 ± 0.21 1.84 ± 0.19  2.10± 0.24  5 12 0.01 ± 0.01 0.31 ± 0.11 0.78 ± 0.23 1.47 ± 0.20  1.46 ±0.19* 10 11 0.00 ± 0.00 0.42 ± 0.17  0.33 ± 0.16* 1.02 ± 0.27* 1.05 ±0.19* 20 12 0.00 ± 0.00 0.48 ± 0.18 0.57 ± 0.14 0.78 ± 0.18* 1.02 ±0.24* 40 12 0.00 ± 0.00 0.12 ± 0.05  0.10 ± 0.04* 0.09 ± 0.06* 0.12 ±0.06* *= Significant difference from vehicle (ANOVA corrected formultiple comparisons, (p ≦ 0.05).The term ANOVA stands for Analysis of Variance.

These results support and confirm the hypothesized anti-neuropathic painactivity of the compound.

Data reported here support and give the necessary scientific basis forthe activity observed earlier in the writhing test and the mouseformalin test. The former data being limited due to the fact that thewrithing test is considered a very unspecific test with some tonicchemically-induced nociceptive aspects that usually gives positiveresults for all psychoactive drug muscle relaxants etc. therefore notbeing specific enough to claim specific activity. In addition, theformer results obtained in the mouse formalin test, lacks clear evidenceof dose relationship and therefore specificity of the observed effectsfor harkoseride. Furthermore, the only and highest dose givingsignificant effects in the first investigation already was found tocause clear behavioral side effects. Therefore, these drugs includechanges in behavior, these drug-related changes cannot be claimed asantinociceptive any longer.

Therefore, only the newly reported data provided here can be consideredan in vivo proven antinociceptive effect of harkoseride, with dosedependency serving as measure of specificity and improvement ofantinociceptive behavior as being unrelated to toxic effects.

EXAMPLE 2

Chronic Constriction Injury (CCI, Bennett-Model)

The effectiveness of harkoseride in reducing spontaneous chronic pain,mechanical allodynia, and thermal hyperalgesia was tested using thechronic constriction injury (CCI) model of peripheral neuropathy, one ofthe best characterized in vivo animal models used to study chronic paindue to peripheral nerve injury. In this model, loose ligatures areplaced around the sciatic nerve, which produces axonal swelling and apartial deafferentation manifested as a significant but incomplete lossof axons in the distal portion of the peripheral nerve. One of theprominent behaviors seen following sciatic nerve ligation is theappearance of hind paw guarding, thought to be an indication of anongoing spontaneous chronic pain. Support for this idea is derived fromreports of increased spinal cord neural activity, and increasedspontaneous neuronal discharge in spinothalamic tract neurons and in theventrobasal thalamus in the absence of overt peripheral stimulation. Inaddition to the appearance of spontaneous pain behaviors, severalabnormalities in stimulus evoked pain occur as a result of CCI,including thermal hyperalgesia and mechanical allodynia. The developmentof these abnormal stimulus-evoked pains has also been reported asoccurring in areas outside the territory of the damaged nerve, areasinnervated by uninjured nerves.

Behavioural tests for spontaneous pain, thermal hyperalgesia, andmechanical allodynia were conducted to evaluate different components ofneuropathic pain. Baseline data for each test was collected prior to anyexperimental procedure; in addition, all animals were tested for thedevelopment of chronic pain behaviours 13-25 days after CCI surgery 1day prior to the day of vehicle (0.04 ml sterile water/10 g body weight)or drug administration and after vehicle/drug administration. Thesequence of the tests was (1) spontaneous pain-related behaviour, (2)mechanical allodynia and (3) thermal hyperalgesia in order to minimisethe influence of one test on the result of the next. The testingprocedures and results are presented separately for each aspect ofchronic pain. Either 0 (vehicle, 0.04 ml/10 g body weight), 5, 10, 20 or40 mg/kg of SPM 927 (n=7-23/group) was administered i.p. 15 minutesbefore the first behavioural test.

Spontaneous pain (ongoing pain without an apparent external stimulus) ofthe ligated paw was assessed for 5 min following a 10 minute acclimationperiod by use of a rating score (weighted behavior score scaled 0-5).

Harkoseride did not change the level of spontaneous pain induced byunilateral chronic constriction injury as shown in Table 2 (weightedpain scores±SEM).

TABLE 2 Spontaneous nociception, CCI model, rat Dose No. of [mg/kg]Animals Baseline Post-op Post-op + Drug 0 23 0 ± 0 1.4 ± 0.15 1.2 ± 0.145 9 0 ± 0 2.0 ± 0.10 1.8 ± 0.18 10 20 0.0019 ± 0.0019 1.5 ± 0.10 1.5 ±0.11 20 8 0 ± 0 1.1 ± 0.17 0.9 ± 0.14 40 10 0.0004 ± 0.0004 1.3 ± 0.120.8 ± 0.28

Thermal hyperalgesia was assessed by means of withdrawal latency inresponse to radiant heat applied to the subplantar surface of theligated rat hind paw. As compared to the baseline latency (s), asignificant decrease in the (postoperative) latency of foot withdrawalin response to the thermal stimulus was interpreted as indicating thepresence of thermal hyperalgesia following chronic constriction injury.

Harkoseride dose dependently reduced chronic constriction injury-inducedthermal hyperalgesia as shown in Table 3 [latencies (s)±SEM].Significant effects were observed only at the highest doses tested (20and 40 mg/kg i.p.) with the maximum effect seen already at 20 mg/kg i.p.

TABLE 3 Thermal hyperalgesia, CCI model, rat Dose No. of [mg/kg] AnimalsBaseline Post-op Post-op + Drug 0 13 9.8 ± 0.74 7.0 ± 0.29 7.3 ± 0.43 57 10.5 ± 0.68  8.1 ± 0.59 9.2 ± 0.98 10 7 9.2 ± 0.68 7.1 ± 0.60 8.1 ±0.59 20 8 10.0 ± 0.70  7.0 ± 0.56  9.7 ± 0.96* 40 8 8.3 ± 0.57 7.4 ±0.48 10.2 ± 0.75* *= Significant difference from vehicle (ANOVAcorrected for multiple comparisons, p ≦ 0.05).

Mechanical sensitivity and allodynia of the ligated rat hind paw wasquantified by brisk foot withdrawal in response to normally innocuousmechanical stimuli as described previously. Responsiveness to mechanicalstimuli was tested with a calibrated electronic Von Frey pressurealgometer connected to an online computerised data collection system. Asignificant decrease in the post operative compared to baseline pressure(g/mm²) necessary to elicit a brisk foot withdrawal in response to thismechanical stimulus is interpreted as mechanical allodynia.

Harkoseride dose dependently reduced the intensity of mechanicalallodynia induced by unilateral nerve ligation as shown in Table 4[pressure (g/mm²)±SEM]. Regression analysis showed a positive linearcorrelation between the dose of Harkoseride and the increase in theamount of force required to produce foot withdrawal.

TABLE 4 Mechanical allodynia, CCI model, rat Dose No. of [mg/kg] AnimalsBaseline Post-op Post-op + Drug 0 20 41.6 ± 2.20 18.8 ± 2.09 20.2 ±1.90  5 11 53.6 ± 3.35 16.4 ± 2.56 21.8 ± 2.34  10 17 42.9 ± 2.55 21.2 ±2.13 29.2 ± 2.85* 20 8 46.1 ± 2.62 24.7 ± 2.78 39.6 ± 3.62* 40 9 48.4 ±3.84 23.9 ± 2.23 43.0 ± 5.48* *= Significant difference from vehicle(ANOVA corrected for multiple comparisons, p ≦ 0.05).

These results support and confirm the hypothesized anti-allodyniaefficacy of Harkoseride. Furthermore this effect is additionally relatedto neuropathic pain and therefore supports the potential clinical use ofthe compound by mimicking the clinical situation of symptom relatedtreatment as close as possible.

Further proof of specificity of the anti-allodynia effect of harkoseridewas given by negative results in the tail flick test excluding typicalopioid-like analgesia of the compound. The former data obtained in micecould be repeated and confirmed in a second species, the rat, byadditional means of more appropriate choice of the doses tested.

EXAMPLE 3

Tail Flick Test, Rat

Harkoseride was additionally tested for potential activity in acutespinal thermal nociception using the tail flick test. In this model ofacute thermal spinal/reflex hyperalgesia radiant heat is applied to theanimal's tail approximately 2 cm from the tip and time latency forwithdrawal reaction is automatically assessed by an algometer, a definedmaximal stimulus time prevents tissue damage. This test is widely usedas an assay for the anti-nociceptive efficacy of pharmacological agentsand is highly predictive of acute analgesic efficacy in humans. Usually,pure analgesics of the opioid type are most active; neither adjuvantslike amitryptilline nor anti-epileptics nor NSAIDs (non-steroidalanti-inflammatory drugs) are active.

Results for 20 and 40 mg/kg harkoseride i.p. are shown in Table 5[percent anti-nociception, calculated as [{(post-druglatency)−(pre-drug-latency)}/{(max. latency)−(predruglatency)}×100]±SEM, n=12/group]. A baseline or pre-drug tail-flicklatency was determined by averaging 5 consecutive measurements taken 2minutes apart. Vehicle (sterile water 0.04 ml/10 g body weight) orharkoseride were then administered and tail flick latencies recorded at10 minute intervals for the next 60 minutes. Even at doses givingmaximum effect in the rat formalin test (see above), harkoseride hadlittle or no effect on the latency of the tail flick reflex.

TABLE 5 Acute thermal hyperalgesia, tail flick, rat Anti-nociceptiveeffect [%] of different Time after doses [mg/kg] of i.p. Harkoseride SPM927 [min] 0 20 40 10 −2.1 ± 3.08  5.0 ± 3.94 −1.6 ± 12.82 20 −0.5 ±3.19  9.7 ± 7.51 −4.3 ± 14.04 30 4.4 ± 4.71 9.7 ± 2.37 −2.3 ± 9.14  4010.4 ± 5.91  1.7 ± 7.42 −4.4 ± 11.44 50 7.6 ± 4.58 5.4 ± 4.12  0.3 ±15.50 60 7.4 ± 6.07 8.1 ± 5.20 −5.5 ± 14.11

Therefore no anti-nociceptive effect of harkoseride was detectable inthe tail-flick test; this supports the hypothesized profile ofharkoseride with highly specific anti-allodynia properties and not beingactive in conditions of acute pain.

EXAMPLE 4

The Anti-Nociceptive Activity of Harkoseride in Comparison withGabapentin

In the following explained study the used harkoseride is hereinafterabbreviated as SPM 927 and gabapentin is hereinafter abbreviated as GBP.

Objective:

The major aim of this study was to assess the anti-nociceptive activityof SPM 927 and GBP in rodent models for inflammatory pain and to comparethe in vivo effects of each drug with each other.

Methods:

Carrageenan-induced mechanical hyperalgesia in rats was induced bysubplantar injection of a 0.1 ml of a 2% carrageenan suspension andmeasured 3 h afterwards by the paw pressure (Randall-Sellito) test.

Subchronic inflammatory nociception in mice was induced by thesubplantar injection of formalin (0.02 ml of a 5% solution). Nociceptivebehavior (paw licking) was measured and quantified between 0 and 5min(acute pain) and between 20 and 30 min (subchronic inflammatory pain)after formalin.

Drugs and experimental design: SPM 927 and GBP were suspended in 1%methylcellulose and administered i.p. at doses of 10 mg/kg, 20 mg/kg and40 mg/kg. Pretreatment time was 30 min before pain measurement. Onegroup of animals served as controls and consequently received aninjection of solvent (10 ml/kg) and another group of animals received areference compound (Carrageenan test: 10 mg/kg indomethacin; Formalintest: 10 mg/kg morphine). Each compound was tested in a separateexperiment and each experiment included a control and a reference group.10 rats per group were used in the Carrageenan test and 6 mice per groupin the formalin test.

Results:

Carrageenan-induced mechanical hyperalgesia in rats: Results aresummarized in the following Table 6.

TABLE 6 VEHICLE VEHICLE non-inflamed inflamed SPM 927 SPM 927 SPM 927Indomethacin paw paw [10] [20] [40] [10] nociceptive 330 ± 16 164 ±15^(a) 324 ± 15^(b) 426 ± 24^(b) 444 ± 13^(b) 384 ± 11^(b) thresholdVEHICLE VEHICLE non-inflamed inflamed GBP GBP GBP Indomethacin paw paw[10] [20] [40] [10] nociceptive 396 ± 15 204 ± 10^(a) 254 ± 39 296 ± 31282 ± 33 370 ± 15^(b) threshold ^(a)indicates a significant differencein comparison with the non-inflamed paw (p < 0.05; Student's t-test)^(b)indicates a significant difference in comparison with the vehicletreated group (p < 0.05; Dunnett's test)

In all three experiments significant mechanical hyperalgesia developedas shown by significant differences in the nociceptive threshold in theinflamed as compared to the non-inflamed paw.

All doses of SPM 927 resulted in a full reversal of Carrageenan-inducedmechanical hyperalgesia.

The antinociceptive of SPM 927 was comparable to that of the referencecompound Indomethacin.

GBP had no significant effect on Carrageenan induced mechanicalhyperalgesia at the doses tested.

Subchronic inflammatory nociception in mice (formalin test): Results aresummarized in the following Table 7.

TABLE 7 SPM 927 SPM 927 SPM 927 Morphine Phase VEHICLE [10] [20] [40][10] nociceptive early  84 ± 16 67 ± 15  69 ± 8 8 ± 8^(a)  6 ± 3^(a)threshold[s] late 119 ± 18 58 ± 16^(a) 128 ± 16 17 ± 17^(a) 10 ± 8^(a)GBP GBP GBP Morphine VEHICLE [10] [20] [40] [10] nociceptive early 106 ±15 98 ± 20 102 ± 17 72 ± 10 8 ± 6^(a) threshold[s] late 111 ± 24 133 ±30  118 ± 13 73 ± 13 0 ± 0^(a) ^(a)indicates a significant difference incomparison with the vehicle treated group (p < 0.05; Dunnett's test)

A clear nociceptive response was induced by formalin. SPM 927 dosedependently suppressed the nociceptive response. The efficacy of SPM 927was similar to that of morphine i.e. a near complete reversal of theformalin-induced nociception. GBP slightly but not significantlyinhibited the nociceptive response induced by formalin

EXAMPLE 5

The following Tables 8 and 9 show the effects of harkoseride (herinafterreferred to as SPM 927), carbamazepine, levetiracetam, gabapentin andmorphine in the neuropathic pain (CHUNG) test in the rat. Eight (8) ratsper group were used.

Table 8 shows the examined effects by tactile stimulation on lesionedpaw.

Table 9 shows the examined effects by thermal stimulation on lesionedpaw.

In general, all compounds showed more pronounced effects on tactilenociceptive stimulation than on thermal nociceptive stimulation, and SPM927 was minimum comparable, but usually more potent than the referencecompounds.

TABLE 8 EFFECTS OF SPM 927, CARBAMAZEPINE, LEVETIRACETAM, GABAPENTIN ANDMORPHINE IN THE NEUROPATHIC PAIN (CHUNG) TEST IN THE RAT (8 RATS PERGROUP) TACTILE STIMULATION (lesioned paw) TREATMENT FORCE INDUCINGPAW-WITHDRAWAL (mg/kg) (g) i.p. −30 min mean ± s.e.m. p value % changeSham control 63.3 ± 4.5 — — Lesioned control 17.4 ± 2.2 *** (a) 0.000−73% (a) SPM 927  (8) 27.2 ± 4.9 NS (b) 0.094 +56% (b) SPM 927 (16) 24.4± 3.0 NS (b) 0.086 +40% (b) SPM 927 (32) 37.6 ± 6.1 ** (b) 0.008 +116% (b) Carbamazepine (16) 21.0 ± 2.3 NS (b) 0.275 +21% (b) Carbamazepine(32) 38.4 ± 8.1 * (b) 0.026 +121%  (b) Carbamazepine (64) 39.2 ± 9.1 *(b) 0.036 +125%  (b) Levetiracetam (16) 23.0 ± 4.0 NS (b) 0.243 +32% (b)Levetiracetam (32) 25.0 ± 5.2 NS (b) 0.199 +44% (b) Levetiracetam (64)19.8 ± 4.1 NS (b) 0.612 +14% (b) Gabapentin (32) 17.2 ± 3.0 NS (b) 0.959 −1% (b) Gabapentin (64) 23.5 ± 4.2 NS (b) 0.219 +35% (b) Gabapentin(128)  33.6 ± 6.7 * (b) 0.038 +93% (b) Morphine (16) 45.9 ± 8.8 ** (b)0.007 +164%  (b) Student's t test (non-paired): NS = Not Significant; *= p < 0.05; ** = p < 0.01; *** = p < 0.001. (a) compared with shamcontrol (b) compared with lesioned control

TABLE 9 EFFECTS OF SPM 927, CARBAMAZEPINE, LEVETIRACETAM, GABAPENTIN ANDMORPHINE IN THE NEUROPATHIC PAIN (CHUNG) TEST IN THE RAT (8 RATS PERGROUP) THERMAL STIMULATION (lesioned paw) TREATMENT PAW-WITHDRAWALLATENCY (mg/kg) (sec) i.p. −30 min mean ± s.e.m. p value % change Shamcontrol 40.6 ± 2.2 — — Lesioned control 16.3 ± 4.4 *** (a) 0.000 −60%(a) SPM 927  (8) 26.1 ± 5.4 NS (b) 0.180 +60% (b) SPM 927 (16) 16.8 ±4.5 NS (b) 0.933  +3% (b) SPM 927 (32) 21.1 ± 5.6 NS (b) 0.512 +29% (b)Carbamazepine (16) 35.6 ± 4.1 ** (b) 0.006 +118%  (b) Carbamazepine (32)22.7 ± 4.3 NS (b) 0.315 +39% (b) Carbamazepine (64) 28.8 ± 6.9 NS (b)0.147 +77% (b) Levetiracetam (16) 19.0 ± 3.6 NS (b) 0.641 +17% (b)Levetiracetam (32) 17.1 ± 2.9 NS (b) 0.882  +5% (b) Levetiracetam (64)26.6 ± 6.0 NS (b) 0.187 +63% (b) Gabapentin (32) 19.3 ± 3.6 NS (b) 0.611+18% (b) Gabapentin (64) 28.5 ± 5.4 NS (b) 0.101 +75% (b) Gabapentin(128)  27.1 ± 5.2 NS (b) 0.135 +66% (b) Morphine (16) 42.4 ± 1.9 *** (b)0.000 +160%  (b) Student's t test (non-paired): NS = Not Significant; **= p < 0.01; *** = p < 0.001. (a) compared with sham control (b) comparedwith lesioned control

1. A method of treating tinnitus aureum in a subject, comprisingadministering to the subject an effective amount of a compound ofFormula I:

wherein: Ar is phenyl which is unsubstituted or substituted with atleast one halo group; Q is lower alkoxy containing 1-3 carbon atoms; andQ₁ is methyl; or a pharmaceutically acceptable salt thereof.
 2. Themethod of claim 1, wherein the compound of Formula (I) orpharmaceutically acceptable salt thereof is in the R configuration. 3.The method of claim 1, wherein, in the compound of Formula I, Ar isunsubstituted phenyl.
 4. The method of claim 1, wherein, in the compoundof Formula I, Ar is phenyl substituted with fluoro.
 5. The method ofclaim 1, wherein the compound of Formula I is(R)-2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceuticallyacceptable salt thereof.
 6. The method of claim 1, wherein the compoundof Formula I is (R)-2-acetamido-N-benzyl-3-methoxypropionamide.
 7. Themethod of claim 6, wherein the compound is administered in a dailydosage amount of about 1 to about 600 mg.
 8. The method of claim 6,wherein the compound is administered in a daily dosage amount of about300 to about 600 mg.
 9. The method of claim 6, wherein the compound isadministered in a daily dosage amount of about 1 to about 300 mg. 10.The method of claim 6, wherein the compound is administered in an oraldosage amount of about 1 to about 600 mg per day.
 11. The method ofclaim 1, wherein the compound or salt thereof is administered in a dailydosage amount of about 1 to about 600 mg.
 12. The method of claim 1,wherein the compound or salt thereof is administered in a daily dosageamount of about 1 to about 300 mg.
 13. The method of claim 1, whereinthe compound or salt thereof is administered in a daily dosage amount ofabout 300 to about 600 mg.
 14. The method of claim 1, wherein thecompound or salt thereof is administered in an oral dosage amount ofabout 1 to about 600 mg per day.